OVERALL DESCRIPTION (Taken directly from the application) In this long-standing program project now in its 20th year, the overall goal remains the same: to achieve a complete control of nephrolithiasis, by (a) seeking pathophysiological elucidation by using molecular, metabolic, physical and physicochemical approaches, and (b) formulating innovative treatments that are safe and effective. In Component I, detailed molecular biological studies will be conducted to identify gene defects responsible for high intestinal calcium absorption and excessive bone loss, in well-characterized probands and kindreds with absorptive hypercalciuria. In Component II, careful biochemical and molecular studies will be performed to unravel multiple steps involved in the regulation of proximal tubular citrate transporter. Component III will represent our continuing efforts toward improved understanding of basic shock wave lithotripsy technology and bioeffects, ultimately directed at finding safer alternative for the surgical: management of symptomatic calculi. In Project 1 of Component IV, our past identification of gene defects in some patients with Type I cystinuria will be expanded to systematically search for gene mutations in other types of cystinuria and remaining patients with Type I cystinuria will be expanded to systematically search for gene mutation in other types of cystinuria and remaining patients with Type I cystinuria. Project 2 of Component IV will test the hypothesis that insulin resistance accounts for the acquired form of gouty diathesis, in contradiction to an unknown genetic defect in the genetic form this entity. In Project 1 of Component V, a randomized trial between potassium-magnesium citrate and placebo will be conducted in patients completing lithotripsy, to test the value of medical treatment post-lithotripsy and to assess the relative utility of this new drug in normocalciuric vs. hypercalciuric patients. In Project 2 of this component, a randomized trial between UroPhos-K (slow-release, neutral potassium phosphate) and Urocit-K )potassium citrate) will be performed in patients with absorptive hypercalciuria, to test the hypothesis that the former drug would be more effective because of its capability for the long-term control of hypercalciuria.